The PSA era is over. In the U.S., widespread serum PSA (prostate-specific antigen) screening and extensive biopsies have led to the detection of ever smaller prostate cancers, such that serum PSA no longer has a correlation with cancer. In today's patients diagnosed with prostate cancer, serum PSA correlates only with prostate weight [i.e., benign prostatic hyperplasia (BPH)]. The loss of any relationship of serum PSA to prostate cancer emphasizes the urgency of finding a new marker for prostate cancer. Any new marker, however, must be proportional to the amount of cancer in the prostate because autopsy studies have shown that prostate cancer is ubiquitous, and by the age of 70, approximately 80% of men have prostate cancer. It is not advisable to attempt to detect all of these cancers, because the relatively small death rate from prostate cancer tells us that many of these cancers are not life threatening. Our previous work has shown that the percentage (%) of Gleason grade 4/5 pattern in the cancer is the strongest prognostic marker currently known. For every 10% increase in grade 4/5 in the index (largest) cancer at the time of radical prostatectomy, there is a 10% biochemical failure rate as measured by a detectable and rising serum PSA. Therefore, we propose that a serum marker proportional to the amount and/or % of Gleason grade 4/5 cancer is critically needed. We will pursue our goal of identifying a serum marker of aggressive prostate cancer through two integrated and comprehensive approaches. Our specific aims are to 1) measure candidate protein markers of aggressive cancer in sera from patients pre- and post- prostatectomy and 2) identify additional candidate serum markers by proteomic analysis of BPH and grade 4/5 cancer tissues. Resources that will contribute towards achieving our goal include archival, fixed, serially sectioned and mapped radical prostatectomy specimens, a bank of well-characterized frozen prostatic tissues, a very large serum bank, comprehensive clinical and histopathologic databases, state-of-the-art technology, and skilled personnel.